Cyclopentane(ene) heptenoic or heptanoic acids and derivatives thereof useful as therapeutic agents

ABSTRACT

The invention relates to 7- 5-hydroxy-2-(hydroxyhydrocarbyl or heteroatom-substituted hydroxy hydrocarbyl)-3-hydroxycyclopentyl(enyl)! heptanoic or heptenoic acids and derivatives of said acids, wherein one or more of said hydroxy groups are replaced by an ether group. The compounds of the present invention are potent ocular hypotensives, and are particularly suitable for the management of glaucoma.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional of U.S. Ser. No. 08/740,883filed Nov. 4, 1996 now U.S. Pat. No. 5,681,848, which is a divisional ofpatent application of U.S. Ser. No. 08/445,842, was filed on Jul. 11,1995 U.S. Pat. No. 5,587,391 which is a divisional of U.S. Ser. No.08/174,535, filed on Dec. 28, 1993, now U.S. Pat. No. 5,545,665.

FIELD OF THE INVENTION

The present invention provides 7- 5-hydroxy-2-(hydroxyhydrocarbyl orheteroatom-substituted hydroxyhydrocarbyl)-3-hydroxycyclopentyl(enyl)!heptanoic or heptenoic acids and amine, amide, ether, ester and alcoholderivatives of said acids, wherein one or more of said hydroxy groupsare replaced by an ether group. The compounds of this invention arepotent ocular hypotensives, and are particularly suitable for themanagement of glaucoma. Moreover, the compounds of this invention aresmooth muscle relaxants with broad application in systemic hypertensiveand pulmonary diseases; with additional application in gastrointestinaldisease, reproduction, fertility, incontinence, shock, inflammation,immune regulation, disorders of bone metabolism, renal dysfunction,cancer and other hypoproliferative diseases.

BACKGROUND OF THE INVENTION

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupillary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Prostaglandins were earlier regarded as potent ocular hypertensives;however, evidence accumulated in the last two decades shows that someprostaglandins are highly effective ocular hypotensive agents and areideally suited for the long-term medical management of glaucoma. (See,for example, Starr, M. S. Exp. Eye Res. 1971, 11, pp. 170-177; Bito, L.Z. Biological Protection with Prostaglandins Cohen, M. M., ed., BocaRaton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., AppliedPharmacology in the Medical Treatment of Glaucomas Drance, S. M. andNeufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505).Such prostaglandins include PGF₂α, PGF₁α, PGE₂, and certainlipid-soluble esters, such as C₁ to C₅ alkyl esters, e.g. 1-isopropylester, of such compounds.

In the U.S. Pat. No. 4,599,353 certain prostaglandins, in particularPGE₂ and PGF₂α and the C₁ to C₅ alkyl esters of the latter compound,were reported to possess ocular hypotensive activity and wererecommended for use in glaucoma management.

Although the precise mechanism is not yet known, recent experimentalresults indicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow Nilsson et al.,Invest. Ophthalmol. Vis. Sci. 28 (suppl), 284 (1987)!.

The isopropyl ester of PGF₂α has been shown to have significantlygreater hypotensive potency than the parent compound, which wasattributed to its more effective penetration through the cornea. In 1987this compound was described as "the most potent ocular hypotensive agentever reported." See, for example, Bito, L. Z., Arch. Ophthalmol. 1051036 (1987), and Siebold et al., Prodrug 5, 3 (1989)!.

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF₂α and its prodrugs, e.g. its1-isopropyl ester, in humans. The clinical potential of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma, is greatly limited by these side effects.

Certain phenyl and phenoxy mono, tri and tetra nor prostaglandins andtheir 1-esters are disclosed in European Patent Application 0,364,417 asuseful in the treatment of glaucoma or ocular hypertension.

In a series of co-pending United States patent applications assigned toAllergan, Inc. prostaglandin esters with increased ocular hypotensiveactivity accompanied with no or substantially reduced side-effects aredisclosed. The co-pending U.S. Ser. No. 386,835 (filed 27 Jul. 1989),relates to certain 11-acyl-prostaglandins, such as 11-pivaloyl,11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF₂α.Intraocular pressure reducing 15-acyl prostaglandins are disclosed inthe copending application U.S. Ser. No. 357,394 (filed 25 May 1989).Similarly, 11,15- 9,15- and 9,11-diesters of prostaglandins, for example11,15-dipivaloyl PGF₂α are known to have ocular hypotensive activity.See the co-pending patent applications U.S. Ser. No. No. 385,645 filed27 Jul. 1990, now U.S. Pat. No. 4,494,274; 584,370 which is acontinuation of U.S. Ser. No. No. 386,312, and 585,284, now U.S. Pat.No. 5,034,413 which is a continuation of U.S. Ser. No. 386,834, wherethe parent applications were filed on 27 Jul. 1989. The disclosures ofthese patent applications are hereby expressly incorporated byreference.

SUMMARY OF THE INVENTION

We have found that certain 7- 5-hydroxy-2-(hydroxyhydrocarbyl orheteroatom-substituted hydroxyhydrocarbyl)-3-hydroxycyclopentyl(enyl)!heptanoic or heptenoic acids and amine, amide, ether, ester and alcoholderivatives of said acids, wherein one or more of said hydroxy groupsare replaced by an ether group are potent ocular hypotensive agents. Wehave further found that such compounds may be significantly more potentthan their respective parent compounds and, in the case of glaucomasurprisingly, cause no or significantly lower ocular surface hyperemiathan the parent compounds.

The present invention relates to methods of treating cardiovascular,pulmonary-respiratory, gastrointestinal, reproductive, allergic disease,shock and ocular hypertension which comprises administering an effectiveamount of a compound represented by the formula I ##STR1## whereineither the cyclopentane radical or the α or ω chain may be unsaturated;R is a hydrocarbyl radical or a heteroatom substituted hydrocarbylradical comprising up to ten carbon atoms and one or more of thehydrogen or carbon radicals in said hydrocarbyl radical may besubstituted with oxygen, sulfur, nitrogen, phosphorus or halogen, e.g.chloro and fluoro; R₁, R₂ and R₃ are selected from the group consistingof hydroxy, hydrocarbyloxy and heteroatom substituted hydrocarbyloxywherein said hydrocarbyl radical comprises up to 20, e.g. 10 carbonatoms; Y represents 2 hydrogen radicals or an oxo radical and Xrepresents a hydroxyl, a hydrocarbylcarboxy, a hydrocarbyloxy, amino ormono or dialkyl amino radical; provided, however, at least one of R₁, R₂and R₃ is a hydrocarbyloxy or heteroatom substituted hydrocarbyloxy,i.e., an ether group and preferably only one of R₁, R₂ and R₃ is anether group, or a pharmaceutically-salt thereof.

Preferably R, R₁, R₂ and R₃ are selected from the group consisting ofalkyl, alkenyl or aryl radicals and heteroatom-substituted derivativesthereof wherein the heteroatoms are as defined above and said radicalshave up to 10 carbon atoms. Said heteroatom-substituted derivatives mayinclude halo, e.g. fluoro, chloro, etc., nitro, amino, thiol, hydroxy,alkyloxy, alkylcarboxyl radicals. Examples of suitable R, R₁, R₂, and R₃radicals are methyl, ethyl, propyl, butyl, propenyl, cyclopentyl,cyclohexyl, phenyl, thienyl, furanyl, pyridyl, etc.

Most preferably, R₁, R₂ and R₃ are selected from the group consisting ofhydroxy and alkyloxy or alkenyloxy radicals having up to 7 carbon atoms.

More preferably the method of the present invention comprisesadministering a compound represented by the formula II ##STR2## whereiny is 0 or 1 to 5, Z is a radical selected from the group consisting ofhalo, e.g. fluoro, chloro, etc., nitro, amino, thiol, hydroxy, alkyloxy,alkylcarboxy, etc. and n is 0 or an integer of from 1 to 3, x and z are0 or 1, and when x is 0, z is 1 and when z is 0, x is 1 and the symbolsR₁, R₂, R₃, and Y are as defined above.

Preferably the compound used in the above method of treatment is acompound of formulas (III or IV). ##STR3## wherein R₁, R₂, R₃, X and Yare as defined above and the hatched and triangular lines are definedbelow.

In a further aspect, the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formulae (I), (II), (III), or (IV) wherein the symbols have the abovemeanings, or a pharmaceutically acceptable salt thereof in admixturewith a non-toxic, pharmaceutically acceptable liquid vehicle.

In a still further aspect, the present invention relates to certainnovel 7- 5-hydroxy-2-(hydroxyhydrocarbyl orhydroxyheteroatom-substituted hydrocarbyl)-3-hydroxycyclopentyl(enyl)!heptanoic or heptenoic acids and amine, amide, ether, ester and alcoholderivatives of said acids, wherein one or more of said hydroxy groupsare replaced by an ether group or a pharmaceutically acceptable salt ofsuch compounds.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a schematic representation of the synthesis of the ethers ofthis invention, i.e., the 9; 11; 15; 9, 11; 9, 15; 11, 15 ethers, etc.

FIG. 2 is a schematic representation of the synthesis of various othercompounds of the invention from said 9, 11 and/or 9,15 ethers of FIG. 1.

FIG. 3 is a schematic representation of the synthesis of 15-acylanalogues of certain of the ethers of the invention.

FIG. 4 is a schematic representation of the synthesis of certain of the5, 6 trans compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In all of the above formulae the dotted lines on bonds between carbons 5and 6 (C-5) of the a chain, between carbons 13 and 14 (C-13) of the wchain, and between carbons 10 and 11 (C-11) of the cyclopentane ring,indicate a single or a double bond which can be in the cis or transconfiguration (Of course, the C-10 and C-11 double bonds being part ofthe cyclopentane ring will exist only as cis double bonds). If two solidlines are used that indicates a specific configuration for that doublebond. Hatched lines at positions C-8, C-9, C-11, C-12 and C-15 indicatethe a configuration. If one were to draw the b configuration, a solidtriangular line would be used.

In the compounds used in accordance with the present invention,compounds having the C-8, C-9, C-11, C-12 or C-15 substituents in the aor b configuration are contemplated.

For the purpose of this invention, unless further limited, the term"alkyl" refers to alkyl groups having from one to ten carbon atoms, theterm "cycloalkyl" refers to cycloalkyl groups having from three to sevencarbon atoms, the term "aryl" refers to aryl groups having from four toten carbon atoms. The term "hydrocarbyl" means radicals having up to 20carbon atoms and the remaining atoms comprising said--hydrocarbylradical are hydrogen. In the "heteroatom-substituted" radicals any ofthe carbon atoms or the hydrogen atoms may be replaced by one of theabove defined heteroatoms. Such hydrocarbyl radicals include aryl,alkyl, alkenyl and alkynyl groups of appropriate lengths, and may bemethyl, ethyl, propyl, butyl, pentyl, or hexyl, or an isomeric formthereof; ethenyl, propenyl, etc.; phenyl, etc.

In FIG. 1 PGF_(2a) or 17-phenyl (18, 19, 20 trinor) PGF_(2a) is reactedwith diazomethane to convert such compounds to the corresponding1-methyl ester. In this scheme R₄ is n-propyl or phenyl. Subsequently,as shown in Reaction 1b and further illustrated in Examples 1 and 3, theabove 1-methyl esters are reacted with an organoiodide, represented byR₁ I, R₂ I or R₃ I, in the presence of Ag₂ O and dimethyl formamide,e.g. at 23° C.

In FIG. 2 the 1-methyl ester, prepared according to the reaction 1b ofFIG. 1, is reacted to provide various compounds of this invention. Asshown in Reaction 2d and Example 7, the 1-methyl ester may be hydrolyzedwith 0.5N aqueous LiOH in tetrahydrofuran (TIF) to yield thecorresponding acid. Alternatively, the 1-methylester may be reduced withLiBH₄ in ethylether, in accordance with Reaction 2c and as illustratedin Example 6, to yield the corresponding alcohol. This alcohol may besubsequently converted into the 5-t-butyl dimethyl siloxy derivative andreacted, in accordance with Reaction 2e, with 2,6-di-t-butyl pyridine inCH₂ Cl₂ and subsequently reacted with methyl triflate (MEOTF) to formthe 1-methoxy derivative. To provide other 1-hydrocarbyloxy esters thealternate Reaction 2e may be utilized whereby the 1-alcohol may bereacted with the hydrocarbyl chloride, R₇ Cl, wherein R₇ is ahydrocarbyl radical comprising up to 20 carbon atoms, e.g. a C1 to C4alkyl chloride, in the presence 4-dimethylaminopyridine (DMAP) intriethylamine and CH₂ Cl₂. Finally, the 1-methylester may be reacted, inaccordance with Reaction 2a and as illustrated in Example 4, with anamine, R₅ R₆ NH, wherein R₅ and R₆ are selected from the groupconsisting of hydrogen and hydrocarbyl radicals, preferably hydrogen andC₁ to C₄ alkyl radicals, in CH₃ OH, for example at a temperature of 55°C., to yield the corresponding amides. Such amides may be subsequentlyreduced with LiAlH₄ in THF, in accordance with Reaction 2b and asillustrated by Example 5, to yield the corresponding amines.

In FIG. 3 the 1-methyl ester, prepared according to the reaction schemeof FIG. 1, is reacted in accordance with Reaction 3a of FIG. 3 and asillustrated by Example 17 to yield the 15-pivaloyl ester of said1-methyl ester. The compound is subsequently reacted in accordance withReaction 3b of FIG. 3 and as illustrated by Example 17a to yield the11-methoxy derivative. This compound may then be converted to the 1-acidin accordance with Reaction 3c, as illustrated by Example 17b, to yieldthe 11-methoxy, 15 pivaloyloxy acid of the invention.

In FIG. 4, the 1-methylester prepared in accordance with the reactionscheme of FIG. 1, is consecutively reacted according to Reactions 1athrough 1c, as illustrated in Example 18 to yield the 5-trans compoundsof this invention.

The following novel compounds may be used in the pharmaceuticalcompositions and the methods of treatment of the present invention.

Methyl 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxycyclopentyl!-5Z-heptenoate

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-heptenoicacid

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-hepten-1-ol

7-5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-heptenoicacid

Methyl 7-5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxycyclopentyl!-5Z-heptenoate

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-hepten-1-pivalate

Methyl 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxycyclopentyl!-5E-heptenoate

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5E-heptenoicacid

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!5E-hepten-1-ol

Methyl 7-3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)cyclopentyl!-5Z-heptenoate

7-3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenoicacid

7-3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!5Z-hepten-1-ol

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-heptenamide

N,N-Dimethyl-7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl!-5Z-heptenamide

Methyl 7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)cyclopentyl!-5Z-heptenoate

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)-cyclopentyl!-5Z-hepten-1-ol

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)cyclopentyl!-5Z-heptenoicacid

Methyl 7-3α,5α-dimethoxy-2β(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenoate

7- 3α,5α-dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenoicacid

7-3α,5α-dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-hepten-1-ol

Methyl 7-3α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxycyclopentyl!-5Z-heptenoate

7-3α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl!-5Z-heptenoicacid

7-3α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl!-5Z-hepten-1-ol

N-Isopropyl-7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxycyclopentyl!-5Z-heptenamide

N-Isopropyl-7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxycyclopentyl!-5Z-heptenamine

N,N-Dimethyl-7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl!-5Z-heptenamine

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl!-5Z-hepten-1-ol

7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl!-5Z-heptenoicacid

Methyl-7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3αpropoxycyclopentyl!-5Z-heptenoate

Methyl-7-3α,5α-dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-heptenoate

7- 3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-heptenoicacid

7-3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-hepten-1-ol

1-Acetoxy-7-3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-heptene

7-3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-1-methoxy-5Z-heptene

7-3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenamide

N-Isopropyl-7-3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)cyclopentyl!-5Z-heptenamide

N-Isopropyl-7-3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)cyclopentyl!-5Z-heptenamide

Methyl-7-3α,5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclopentyl!-5Z-heptenoate

7- 3α,5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclopentyl!-5Z-heptenoicacid

Methyl 7-3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenoate

7-3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-hepten-1-ol

7-3α-Butoxy-5α-hydroxy-2β-3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenoicacid

N-Isopropyl-7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-propoxycyclopentyl!-5Z-heptenamide

7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl!-5Z-heptenamide

Isopropyl-7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-propoxycyclopentyl!-5Z-heptenoate

7-3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-heptenamide

Isopropyl-7-3α,5α-dihydroxy-2β-(3α-methoxy-1E-octenyl)cyclopentyl!-5Z-heptenoate

Methyl-7-3α,5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)cyclopentyl!-5Z-heptenoate

7-3α,5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)-cyclopentyl!-5Z-heptenoicacid

7-3α,5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)cyclopentyl!-5Z-heptenamide

A pharmaceutically acceptable salt is any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. Such salts are those formed withpharmaceutically acceptable cations, e.g., alkali metals, alkali earthmetals, etc.

Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable salt thereof, asan active ingredient, with conventional ophthalmically acceptablepharmaceutical excipients, and by preparation of unit dosage formssuitable for topical ocular use. The therapeutically efficient amounttypically is between about 0.0001 and about 5% (w/v), preferably about0.001 to about 1.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventional,pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable.

Accordingly, buffers include acetate buffers, citrate buffers, phosphatebuffers and borate buffers. Acids or bases may be used to adjust the pHof these formulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace of or in conjunction with it.

The ingredients are usually used in the following amounts:

    ______________________________________                                        Ingredient         Amount (% w/v)                                             ______________________________________                                        active ingredient  about 0.001-5                                              preservative       0-0.10                                                     vehicle            0-40                                                       tonicity adjustor  0-10                                                       buffer             0.01-10                                                    pH adjustor        q.s. pH 4.5-7.5                                            antioxidant        as needed                                                  surfactant         as needed                                                  purified water     as needed to make                                                             100%                                                       ______________________________________                                    

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses.

Especially preservative-free solutions are often formulated innon-resealable containers containing up to about ten, preferably up toabout five units doses, where a typical unit dose is from one to about 8drops, preferably one to about 3 drops. The volume of one drop usuallyis about 20-35 ml.

The invention is further illustrated by the following non-limitingExamples.

EXAMPLE 1 Methyl 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3-methoxycyclopentyl!-5Z-heptenoate

In accordance with Reaction 1b of Scheme 1, 300 mg. (0.815 mmols) of the1-methylester of PGF₂α were dissolved in 1.0 mL of dimethylformamide(DMF). To this solution was added 150.5 mg. (0.649 mmol) of Ag₂ O and173.6 mg. (1.22 mmol) of methyliodide (MeI) and the resulting solutionwas stirred at 23° C. to obtain (8% yield) of the named compound inadmixture with the 9-mono (4% yield), 15-mono and 11, 15 bis (14% yield)methyl ethers of the 1-methylester of PGF₂α. (The compounds obtained inadmixture with the named compound may also be referred to as the5α-methoxy, 2β-(3α-methoxy-1E-octenyl) and2β-(3α-methoxy-1E-octenyl)-3αmethoxy analogues of the named compound,respectively. The ethers were separated using high pressure liquidchromatography (HPLC) and eluting the admixture with a 1 to 1 mixture ofhexane (hex) and ethylacetate (EtOAc) over a Whatman PARTISIL 10 PAKcolumn.

EXAMPLE 1a Methyl-7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxycyclopentyl!-5Z-heptenoate.

The named compound may be prepared by substitution of n-propyliodide formethyl iodide in the procedure of Example 1.

EXAMPLE 1b Methyl-7-3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenoate

The named compound may be prepared by substitution of ethyliodide formethyl iodide in the procedure of Example 1.

EXAMPLE 1c Methyl-7-3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl!-cyclopentyl!-5Z-heptenoate

The named compound may be prepared by substitution of n-butyliodide formethyl iodide in the procedure of Example 1.

EXAMPLE 1d Methyl-7-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)-cyclopentyl!-5Z-heptenoate

The procedure of Example 1 is repeated using allyliodide in place ofmethyliodide to yield the named compound.

EXAMPLE 2 Isopropyl 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxycyclopentyl!-5Z-heptenoate

The procedure of Example 1 was repeated except that the 1-isopropylesterof PGF₂α was utilized as the reactant in place of the correspondingmethyl ester to yield a reaction solution containing an admixture ofmono and bis methyl ethers. The reaction solution was diluted with CH₂Cl₂ and filtered through Celite. The filtrate was concentrated undervacuum, diluted with ethylether (Et₂ O) and washed twice with water. Theorganic layer was dried over anhydrous MgSO₄, filtered and concentratedunder vacuum. The residue was purified by flash column chromatography(FCC) with an eluant of 1 to 1 hex/EtOAc to yield 120 mg. (59% yield) ofthe named compound and the 15-methyl ether analogue, thereof. 80% of thepurified mixture was the named compound.

EXAMPLE 3 Isopropyl 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxycyclopentyl!-5Z-heptenoate

20 mg. (0.050 mmol) of PGF₂α was combined with 47 mg (0.252 mmol ofO-isopropyl N,N'-diisopropyl isourea in 1.0 mL of benzene and heated at85° C. for 20 hours. The reaction mixture was concentrated in vacuo andthe residue was purified by FCC using a 3 to 1 mixture of hexane andEtOAc to yield 16.3 mg. (74% yield) of the 11-isopropylester of PGF₂α.The named compound may be prepared from said 11-isopropyl ester bysubstitution of propyliodide for methyliodide in the procedure ofExample 2.

EXAMPLE 4N-Isopropyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxycyclopentyl!-5Z-heptenamide

In accordance with Reaction 2a of FIG. 2, 220 mg. (0.5759 mmol) of thecompound of Example 1 were mixed with 549 mg (5.759 mmol) ofisopropylamine hydrochloride in 6.0 mL of isopropylamine and heated in asealed tube for 72 hours at 75° C. The reaction mixture was cooled toroom temperature, diluted with EtOAc and washed with water. The organiclayer was treated as in Example 2 to yield 23.5 mg (10% yield) of thenamed compound.

EXAMPLE 4aN,N-Dimethyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl!-5Z-heptenamide

The named compound is prepared in accordance with the procedure ofExample 4 by using methylamine hydrochloride in methylamine.

EXAMPLE 4bN-Isopropyl-7-(3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenamide

The named compound is prepared by substituting the compound of Example1b in the process of Example 4.

EXAMPLE 4cN-Isopropyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-propoxy-cyclopentyl!-5Z-heptenamide

The named compound is prepared by substituting the compound of Example1a in the process of Example 4.

EXAMPLE 4dN,N-Dimethyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl!-5Z-heptenamide

Dimethylamine (˜5 ml) was condensed in a tube containing 100 mg (0.1639mmol) of the 5-t-butyldimethylsiloxy, 3-methoxy derivative of PGF₂α,methylester dissolved in 6.0 mL of CH₃ OH. The resultant solution wasstirred in a sealed glass tube for 48 hours and concentrated i-n vacuo.The residue diluted with THF (1.0 mL) and treated with Bu₄ NF (0.26 mLof a 1.0M solution, 0.262 mmol) at 23° C. After 16 hours, the reactionwas diluted with Et₂ O and washed with H₂ O. The organic portion wasdried (MgSO₄), filtered and concentrated in vacuo. FCC (100% EtOAcfollowed by 9:1 CH₂ Cl₂ /MeOH) gave 24.2 mg. (39%) of the product.

EXAMPLE 5N-Isopropyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl!-5Z-heptenamine

In accordance with Reaction 2b of FIG. 2, 75 mg of the compound ofExample 4, dissolved in 2.0 mL of tetrahydrofuran (THF) were treatedwith 34.6 mg. (0.9165 mmol) of lithium aluminum hydride (LAH) at 23° C.After 24 hours, the reaction mixture was quenched with 2.0N NaOH andextracted with EtOAc. The organic layer was dried over anhydrous MgSO₄,filtered and concentrated under vacuum. The residue was purified withFCC using a 6:1:0.1 mixture of CH₂ Cl₂ /MeOH/NH₄ OH to yield 19.0 mg.(26% yield) of the named compound.

EXAMPLE 5aN,N-Dimethyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl!-5Z-heptenamine

The named compound is prepared by substitution of the compound ofExample 4a in the procedure of Example 5.

EXAMPLE 67-(5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-hepten-1-ol

In accordance with Reaction 2c of FIG. 2, 20.2 mg (0.0529 mmol) of thecompound of Example 1 were dissolved in 1.5 mL of Et₂ O and treated with2.3 mg (0.105 mmol) of LiBH₄ to yield a reaction mixture comprising thenamed product. The resulting product was purified by FCC with a 1 to 1mixture of hex/EtOAc followed by 100% EtOAc to yield 16.3 mg. (87%) ofthe named compound.

EXAMPLE 6a 7-3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-hepten-1-ol

The named compound is prepared by substituting the compound of Example1b in the process of Example 6.

EXAMPLE 6b 7-3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl-5Z-hepten-1-ol

The named compound is prepared by substituting the compound of Example1c in the process of Example 6.

EXAMPLE 6c 7-3α-Propoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-hepten-1-ol

The named compound is prepared by substituting the compound of Example1(a) in the process of Example 6.

EXAMPLE 6d 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)-cyclopentyl!-5Z-hepten-1-ol

The procedure of Example 6 is repeated using the compound of Example1(d) as the starting material to yield the named compound.

EXAMPLE 7 7-5α-Hydroxy-1β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-heptenoicacid

40 mg (0.1047 mmol) of the compound of Example 1 were dissolved in amixture of 0.31 mL of 0.5N aqueous LiOH and 0.62 mL of THF in accordancewith Reaction 2d of Scheme 2. After the reaction mixture was acidifiedwith 10% aqueous citric acid and extracted with CH₂ Cl₂. The organicportion was dried (Na₂ SO₄), filtered and concentrated in vacuo. Theresidue was purified by FCC using a 95 to 5 mixture of EtOAc and MeOH toyield 28.6 mg. (75% yield) of the named compound.

EXAMPLE 7a 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl!-5Z-heptenoicacid

The named compound is prepared by substituting the compound of Example1a in the procedure of Example 7.

EXAMPLE 7b 7-3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenoicacid

The named compound is prepared by substituting the compound of Example1b in the procedure of Example 7.

EXAMPLE 7c 7-3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Zheptenoic acid

The named compound is prepared by substituting the compound of Example1c in the procedure of Example 7.

EXAMPLE 7d 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)-cyclopentyl!-5Z-heptenoicacid

The named compound is prepared by substituting the compound of Example1d in the procedure of Example 7.

EXAMPLE 8 7-5α-Hydroxy-2β(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-heptenamide

According to the procedures described for Example 4, the compound ofExample 1 is reacted with NH₄ Cl dissolved in NH₃ to yield the namedcompound.

EXAMPLE 8a 7-3α-Ethoxy-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenamide

In accordance with Example 8, 100 mg (0.252 mmol) of the compound ofExample 1(b) is reacted with 135 mg (2.52 mmol) of NH₄ Cl dissolved in 5mL of NH₃ to give the named compound in 69% yield.

EXAMPLE 8b 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl!-5Z-heptenamide

In accordance with Example 8, 52 mg (0.127 mmol) of the compound ofExample 1(a) is reacted with 68 mg (1.27 mmol) of NH₄ Cl dissolved in4.5 mL of NH₃ to give the named compound in 86% yield.

EXAMPLE 9 7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-1-pivaloyloxy5Z-heptene

The 1-t-butyldimethylsilyl ester of 3-methoxy PGF₂α and 5.2 mg (0.239mmol) of LiBH₄ was dissolved in 1.0 mL of ethylether and stirred for 16hours at 23° C. The reaction mixture was quenched with 2.0N aqueous NaOHand extracted with CH₂ Cl₂. The organic portion was dried over anhydrousNa₂ SO₄, filtered and concentrated under vacuum. The residue wasdissolved in 0.5 mL of pyridine and cooled to 0° C. 17.7 uL (0.143 mmol)of trimethylacetyl chloride were added and after 24 hours the reactionwas diluted with EtOAc, washed with saturated aqueous NH₄ Cl and brineand dried over hydrous MgSO₄. The dried product was filtered andconcentrated under vacuum before purifying by use of FCC and a 1 to 1mixture of hexane and EtOAc to yield 15.9 mg (31% yield of the namedcompound).

EXAMPLE 10 7-3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-1-methoxy-5Z-heptene

In accordance with Reaction 2e of Scheme 2, a solution of the compoundof Example 6 and 0.46 mL 2, 6-di-t-butylpyridine (2.058 mmol) in 2.0 mLCH₂ Cl₂ was treated with methyl triflate (194 ul, 1.715 mmol) andstirred for 48 hours at 23° C. The reaction mixture was quenched withsaturated aqueous NaHCO₃ and extracted with CH₂ Cl₂. The combinedorganic portion was dried over anhydrous Na₂ SO₄, filtered andconcentrated in vacuo. The residue was diluted with 2.0 mL of THF and1.4 mL of a 1.0M solution of Bu₄ NF in THF. After 16 hours, the reactionwas diluted with EtOAc and washed with H₂ O. The organic portion wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo. Treatingby FCC with 1:1 hex/EtOAc gave 66.1 mg (53% yield) of the namedcompound.

EXAMPLE 11 1-Acetoxy-7-3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)cyclopentyl!-5Z-heptene

1-Acetoxy-7-3α,5α-t-butyldimethylsiloxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-hepteneis reacted with Bu₄ NF in THF at room temperature to yield the namedcompound.

EXAMPLE 12 Methyl 7-3α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxycyclopentyl!-5Z-heptenoate

The named compound is prepared in accordance with the procedure ofExample 1.

EXAMPLE 12a 7-3α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl!-5Z-heptenoicacid

The named compound is prepared by reacting the compound of Example 12 inaccordance with the process of Example 7.

EXAMPLE 12b 7-3α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl!-5Z-hepten-1-ol

The named compound is prepared by reacting the 1-t-butyl dimethylsiloxyester of the compound of Example 12(a) in accordance with the process ofExample 6.

EXAMPLE 13 7-3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-hepten-1-ol

The 15-monomethyl ether of Example 1 is reacted in accordance with theprocess of Example 6 to yield the named compound.

EXAMPLE 13a 7-3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-heptenoicacid

The 15-monomethyl ester of Example 1 is reacted in accordance with theprocess of Example 7 to yield the named compound.

EXAMPLE 13b Isopropyl-7-3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)cyclopentyl!-5Z-heptenamide

The 15-monomethyl ester of Example 1 is reacted in accordance with theprocess of Example 4 to yield the named compound.

EXAMPLE 13c 7-3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-heptenamide

The 15-monomethyl ester of Example 1 is reacted in accordance with theprocess of Example 8 to yield the named compound.

EXAMPLE 14 Methyl-7-3α-5α-Dihydroxy-2β-ethoxy-1E-octenyl)-cyclopentyl!-5Z-heptenoate

The named compound is prepared in accordance with the process of Example1 by replacing methyliodide with ethyl iodide.

EXAMPLE 14a 7-3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclopentyl!-5Z-heptenoic acid

The named compound is prepared by reacting the compound of Example 14 inaccordance with the process of Example 7.

EXAMPLE 14b N-Isopropyl-7-3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)cyclopentyl!-5Z-heptenamide

The named compound is prepared by reacting the compound of Example 14 inaccordance with the process of Example 4.

EXAMPLE 14c 7-3α-5α-Dihydroxy-2β-3α-ethoxy-1E-octenyl)-cyclopentyl!-5Z-heptenamide

The named compound is prepared by reacting the compound of Example 14 inaccordance with the process of Example 8.

EXAMPLE 15 Methyl-7-3α-5α-Dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenoate

The named compound is isolated from the reaction product of Example 1.

EXAMPLE 15a 7-3α-5α-Dimethoxy-2β-(3β-hydroxy-1E-octenyl)-cyclopentyl!-5Z-heptenoicacid

The named compound is prepared by substituting the 3, 5-dimethylether ofExample 15 in the process of Example 7.

EXAMPLE 15b 7-3α-5α-Dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl!-5Z-hepten-1-ol

The named compound is prepared by substituting the 3, 5-dimethylether ofExample 15 in the process of Example 6.

EXAMPLE 16 Methyl-7-3α-5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)-cyclopentyl!-5Z-heptenoate

The named compound is prepared according to the process described inExample 1 by substituting the 1-methylester of 17-phenyl, 18, 19,20-trinor PGF₂α for the 1-methylester of PGF₂α.

EXAMPLE 16a 7-3α-5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)cyclopentyl!-5Z-heptenoicacid

The named compound is prepared by substituting the compound of Example16 in the process of Example 7.

EXAMPLE 16b 7-3α-5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)cyclopentyl!-5Z-heptenamide

The named compound is prepared by substituting the compound of Example16 in the process of Example 8.

EXAMPLE 17 Methyl 7-3α,5αDihydroxy-2β(3α-pivalyl-1E-octenyl)-cyclopentyl!-5Z-heptenoate

PGF₂α (40.4 mg 0.114 mmol) was suspended in Et₂ O (1 mL) and cooled to0°. A solution of CH₂ N₂ in Et₂ O was added dropwise to the abovesuspension until a yellow color persisted. The solution was warmed to25° for 30 minutes before concentration to yield the PGF₂α methyl esteras an oil. The crude ester was combined with 14 mg., (0.137 mmol)n-butyl boronic acid (BuB(OH)₂) in 0.25 mL of CH₂ Cl₂ and heated atreflux temperature for 30 minutes. The reaction mixture was concentratedand the residue dissolved in dry benzene. The benzene was evaporatedunder reduced pressure. The process was repeated twice to remove tracesof water present from the reaction, leading to boronate ester, which wassubsequently dissolved in 0.2 mL of dry pyridine and treated withpivalyl chloride (0.043 mL, 0.34 mmol) and 4-DMAP (about 1 mg). Thereaction mixture was stirred at 25° for 14 h before being concentrated.The residue was dissolved in EtOAc (10 mL) and washed with 10% citricacid (7 mL).

The aqueous phase was extracted with EtOAc and the combined organicextracts were washed with brine, dried over anhydrous MgSO₄, filteredand concentrated. The residue was dissolved in MeOH (3 mL) and stirredat 25 for 2 h. The solvent was removed and replaced with fresh MeOH.This process was repeated once more. After removal of solvent, theresidue was purified by chromatography (silica, 50-60% EtOAc/hexane) toyield the named product as an oil.

EXAMPLE 17a Methyl-7-5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-heptenoate

The named compound is prepared by substituting compound of Example 17for the 1-methylester of PGF₂α in the process of Example 1. (SeeReaction 3b of FIG. 3.)

EXAMPLE 17b 7-5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy-cyclopentyl!-5Z-heptenoicacid

The named compound is prepared by substituting the compound of Example17a in the process of Example 7. (See Reaction 3c of FIG. 3.)

EXAMPLE 18 Methyl-7-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxycyclopentyl!-5E-heptenoate

987 mg (2.68 mmol) of the 1-methyl ester of PGF₂α was mixed with 1.43 g(13.41 mmol) of 2, 6-lutidine and 2.48 g (9.38 mmol) oft-butyldimethylsiloxytriflate (TB)(CH₃)SiOSO₂ CF₃ ! in 13.4 mL of CH₂Cl₂ and the solution was stirred for 16 h to yield thetri-(t-butyldimethylsiloxy) ester of the 1-methyl ester of PGF₂α. (SeeReaction 4a of FIG. 4.) The triester was purified by elution (using FCCtechniques) with a 30 to 1. solution of hexane and EtOAc 312 mg (0.439mmols) of the resulting triester was combined with 2.7 mg (0.0088 mmol)of diphenylsulfide in 4.4 mL of benzene and the resulting solution wasstirred under long wave UV light exposure for 12 hours. (See Reaction 4bof FIG. 4.) The resulting solution was concentrated under vacuum andpurified by elution, as above, with a 20 to 1 solution of hexane andEtOAc to yield 296.1 mg (95% yield) of the 5-trans triester. 318 mg(0.447 mmol) of the 5-trans triester were combined with 2.7 mL of a 1.0Msolution of Bu₄ NP in THF and 4.4 mL of THF. The solution was stirredovernight at 23° C., diluted with EtOAc, washed with H₂ O and brine andthe organic portion was filtered, concentrated under vacuum andpurified, using FCC techniques and 100% EtOAc. to yield 123.3 mg (75%yield) of the triol of the 5-trans 1-methyl ester of PGF₂α.

The triol was substituted in the process of Example 1 to yield the namedcompound. (See Reaction 4c of FIG. 4.)

EXAMPLE 18a 7-5α-Hydroxy-2α-(3α-Hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5E-heptenoicacid

The named compound is prepared by substituting the compound of Example18 in the process of Example 7.

EXAMPLE 18b 7-5α-Hydroxy-2β-(3α-Hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl!-5E-hepten-1-ol

The named compound is prepared by substituting the compound of Example18 in the process of Example 6.

EXAMPLE 19 Methyl-7-3α-methoxy-5α-hydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-heptenoate

The named compound is isolated from the reaction product of Example 1.

EXAMPLE 19a 7-3α-methoxy-5α-hydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-heptenoicacid

The named compound is prepared by substituting the dimethylether ofExample 19 in the process of Example 7.

EXAMPLE 19b 7-3α-ethoxy-5α-hydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl!-5Z-hepten-1-ol

The named compound is prepared by substituting the dimethylether ofExample 19 in the process of Example 6.

EXAMPLE 20 EFFECTS ON INTRAOCULAR PRESSURE

The effects of certain of the above examples on intraocular pressure areprovided in the following Table 1. The compounds were prepared at thesaid concentrations in a vehicle comprising 0.1% polysorbate 80 and 10mnM TRIS base. Dogs were treated by administering 25 ul to the ocularsurface, the contralateral eye received vehicle as a control.Intraocular pressure was measured by application pneumatonometry. Dogintraocular pressure was measured immediately before drug administrationand at 4 hours thereafter.

The examples which show excellent IOP-lowering effect include Examples1, 1a, 1b; 6 and 6a wherein the 11 position is substituted with a loweralkyl ether, i.e. a C₁ to C₃ alkyl ether and the 1-position is a loweralkyl ester, e.g. a methyl ester, or an alcohol group. Furthermore, acomparison of Example 1 and 18 shows that the 5-trans or 5-cis isomersare substantially similar in their IOP-lowering effect. Finally, the 9and 15-substituted lower alkyl ether derivatives wherein the 1-positionis substituted with a lower alkyl ester group are also very effective inlowering IOP. (Compare Examples 12 and the 15-monoester of Example 1.)In contrast, various derivatives wherein the 11-position is substitutedwith a lower alkyl ether group and the 1-position is an add or an aminogroup showing lower effect in lowering IOP at a concentration of 0.1%.(See Examples 4a, 4b, 4c, 5, 7d, 18a, 19a and 19b.) However, it isbelieved that higher concentrations would have greater effect inlowering IOP.

In Table 1, hyperemia is measured by visual estimation. Slight hyperemiawould be given a value between 0 and 0.5; moderate hyperemia would begiven a value from 0.5 to 1.0 and severe hyperemia would be given avalue of greater than 1.0. Miosis would be evaluated as 0 (nothing),slight (slite) or pinpoint (pin), i.e., the pupil would be the size of apinpoint.

                  TABLE 1                                                         ______________________________________                                                                     HYPEREMIA/                                       EXAMPLE         DOG IOP      MIOSIS                                           ______________________________________                                        1               0.01/+3.0    0.03/0                                                           0.1%/-6.2    0.50/pin                                         6               0.01/-1.6    0.08/0                                                           0.1%/-5.7    0.75/pin                                         17a             0.1%/-1.3    0.03/slite                                       17              0.1%/-2.5    0.82/pin                                         9               0.1%/-2.5    0.17/slite                                       18              0.01/0       0.08/slite                                                       0.1%/-6.3    0.03/slite                                       18a             0.1%/0.0     0/0                                              18b             0.1%/-3.0    0.03/slite                                        1b             0.1%/-5.2    0.44/pin                                          7b             0.1%/-3.9    0.75/pin                                          6a             0.1%/-6.5    0.03/pin                                                         01%/0.0                                                       8               0.1%/-3.3    0.56/pin                                          4a             0.1%/0.0     0.33/slite                                        1d             0.1%/-3.8    0.66/pin                                          6d             0.1%/-2.3    0.58/pin                                          7d             0.1%/0.0     0.31/pin                                         19              0.1%/-2.4    0.75/pin                                         19a             0.1%/0.0     0.04/0                                           19b             0.1%/0.0     0/slite                                          12              0.01/-3.3    0/slite                                                          0.1%/-7.8    0.53/pin                                         12a             0.1%/-2.8    0.25/slite                                       12b             0.1%/-4.2    0/slite                                          5               0.1%/0.0     0.08/0                                            6c             0.1%/-2.0    0.29/slite                                        7a             0.1%/-3.9    0.54/pin                                                         0.01/0       0.62/slite                                        1a             0.1%/-7.6    0.83/pin                                                         0.01/0       0.29/slite                                       1               0.1%/-7.8    0.89/pin                                         (15-mono ester) 0.01/2.0     0.83/pin                                                         0.1%/-4.5    1.34/pin                                         11              0.1%/-2.9    0.42/slite                                       10              0.1%/-1.8    0/0                                               8a             0.1%/0       0.29/pin                                                         0.1%/-2.9    0.21/pin                                          4b             0.1%/0       0.08/slite                                       13b             0.1%/-3.9    0.5/pin                                          14              0.1%/-4.5    0.50/pin                                          1c             0.1%/-4.4    1.17/pin                                          6b                                                                            7c             0.1%/-1.6    0.70/0                                            4c             0.1%/0       0/0                                               8b             0.1%/-3.8    0.79/pin                                          2a             0.1%/-1.8    0.47/pin                                         13c             0.1%/-3.2    0.59/pin                                                         0.01%/-4.0   0.44/pin                                         14d             0.1%/-2.7    0.46/pin                                                         0.1%/-5.1    0.81/pin                                         2               0.1%/-4.2    0.56/pin                                         16a             0.1%/-3.8    ND/pin                                           16b             0.1%/-4.4    0.47/pin                                         ______________________________________                                    

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent from one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions.

Similarly, different pharmaceutical compositions may be prepared andused with substantially the same results. Thus, however detailed theforegoing may appear in text, it should not be construed as limiting theoverall scope hereof; rather, the ambit of the present invention is tobe governed only by the lawful construction of the appended claims.

I claim:
 1. A method of treating ocular hypertension which comprisesapplying to the eye an amount sufficient to treat ocular hypertension ofa compound of formula (I) ##STR4## wherein either the cyclopentane(ene)radical or the α or ω chain may be unsaturated; R is thienyl; R₁, R₂ andR₃ are selected from the group consisting of hydroxy and hydrocarbyloxyradicals wherein said hydrocarbyloxy radical comprises up to 20 carbonatoms; Y represents 2 hydrogen radicals or an oxo radical and Xrepresents a hydroxyl, a hydrocarbylcarboxy, a hydrocarbyloxy, an aminoor a mono or dialkyl amino radical; provided, however, at least one ofR₁, R₂ and R₃ is a hydrocarbyloxy radical.
 2. The method of claim 1wherein in said compound of formula (I) one of R₁, R₂, or R₃ is alkyloxyand the others are hydroxy radicals.
 3. An ophthalmic solutioncomprising a therapeutically effective amount of a compound of formula(I) ##STR5## wherein either the cyclopentane(ene) radical or the α or ωchain may be unsaturated; R is thienyl; R₁, R₂ and R₃ are selected fromthe group consisting of hydroxy and hydrocarbyloxy radicals wherein saidhydrocarbyloxy radical comprises up to 20 carbon atoms; Y represents 2hydrogen radicals or an oxo radical and X represents a hydroxyl, ahydrocarbylcarboxy, a hydrocarbyloxy, an amino or a mono or dialkylamino radical; provided, however, at least one of R₁, R₂ and R₃ is ahydrocarbyloxy radical.
 4. The ophthalmic solution of claim 3 comprisingat least one ingredient selected from the group of an ophthalmicallyacceptable preservative, buffer system, antioxidant and chelating agent.5. The ophthalmic solution of claim 3 wherein in said compound offormula (I) one of R₁, R₂, or R₃ is alkyloxy and the others are hydroxyradicals.
 6. A pharmaceutical product, comprisinga container adapted todispense its contents in metered form; and an ophthalmic solutiontherein, as defined in claim
 3. 7. A compound of the formula (I)##STR6## wherein either cyclopentane(ene) radical or the α or ω chainmay be unsaturated; R is thienyl; R₁, R₂ and R₃ are selected from thegroup consisting of hydroxy and hydrocarbyloxy radicals wherein saidhydrocarbyl radical comprises up to 20 carbon atoms; Y represents 2hydrogen radicals or an oxo radical and X represents a hydroxyl, ahydrocarbylcarboxy, a hydrocarbyloxy, an amino or a mono or dialkylamino radical; provided, however, at least one of R₁, R₂ and R₃ is ahydrocarbyloxy radical.
 8. A compound according to claim 7 wherein insaid compound of formula (I) one of R₁, R₂, or R₃ is alkyloxy and theothers are hydroxy radicals.